The balancing of energy expenditure and food intake plays a critical role in the control of body weight. Heat generation from uncoupling activity in mitochondria is responsible for a significant portion of energy expenditure, and therefore regulation of uncoupling activities provides a direct target for the treatment of obesity.
It is known that uncoupled mitochondrial respiration in brown adipose tissue (BAT) plays an important role in the regulation of energy balance in rodents.
Bouillaud et al. (1986, J. Biol. Chem. 261(4): 1487–1490) disclose a rat cDNA clone which encodes rat uncoupling protein 1 (UCP1). Rat UCP1 is a mitochondrial inner membrane protein synthesized in the cytosol from a nuclear encoded transcript which is expressed in brown adipose tissue.
Bouillaud et al. (1988, Biochem. Biophys Res. Comm. 157: 783–792) disclose a genomic clone encoding rat UCP1.
Nicholls and Locke (1984, Physiol. Rev. 64: 1–64) review UCP1, noting that the rat 32 kD protein forms a proton channel through the mitochondrial inner membrane and is active in uncoupling ATP synthesis from heat production in BAT.
Jacobsson et al. (1985, J. Biol. Chem. 260: 16250–16254) disclose cDNA clones for mRNA isolated from mouse brown adipose tissue. Mouse ucp1 mRNA was shown to be induced in brown adipose tissue by exposure to cold.
Kozak et al. (1988, J. Biol. Chem. 263: 12274–12277) disclose the genomic clone encoding mouse UCP1.
Cassard et al. (1990, J. Cell. Biochem. 43: 255–264) discloses the genomic clone for human ucp1, as well as the deduced amino acid sequence for human UCP1. The authors show that rat and human UCP1 are 79% homologous at both the nucleotide and amino acid level.
UCP1 activity in thermogenesis and uncoupled energy dissipation is limited to brown adipose tissue. Therefore, it is not expected that UCP1 is actively involved in the cause and effect of body weight indications such as obesity and diabetes in vertebrates such as humans, which contain limited amount of brown fat.
Fleury et al. (1997, Nature Genetics 15: 269–272) disclose a gene encoding both a mouse and human mitochondrial uncoupling protein, designated mouse UCP2 and human UCP2, respectively. The deduced human amino acid sequence encodes a 33 kD protein which is approximately 95% homologous to the mouse protein at the amino acid level. As with human UCP1, human UCP2 comprises 3 mitochondrial carrier protein motifs and an ATP binding site. The authors show a wide range of tissue specific expression of the human ucp2 gene, including skeletal muscle, lung, heart, placenta, stomach, as well as immune systems tissue such as spleen, thymus, leukocytes, macrophages and bone marrow. The authors mapped the human ucp2 gene to chromosome 11, which has been linked to obesity and hyperinsulinaemia in the mouse.
It would be advantageous to identify a gene encoding an additional human uncoupling protein wherein expression is for the most part limited to skeletal muscle. A nucleic acid molecule expressing an additional human uncoupling protein in such a specific manner would be extremely useful in screening for compounds acting as a modulator of to obesity and hyperinsulinaemia. Such a compound or compounds will be useful in controlling obesity as well as deleterious indications associated with obesity, such as diabetes. Additionally, such a nucleic acid molecule will be useful in gene therapy applications to overcome the deleterious effects of obesity and obesity-related complications, such as diabetes. The present invention addresses and meets this need.